PROJECT SUMMARY/ABSTRACT In response to FOA PAR-17-029 ?Dynamic interactions between systemic or non-neuronal systems and the brain in aging and in Alzheimer?s disease (AD)?, we propose to continue our studies (R01AG039452-6) aimed at understanding the role of pericytes in the pathogenesis and treatment of AD-like vascular, neuronal, amyloid-? (A?) and tau disorders using new pericyte-specific animal models and human cranial pericytes derived from pluripotent stem cells via a neural crest cells (NCC) intermediate (termed below iPSC-PC) in collaboration with Dr. Ruchi Bajpai. Pericytes are brain capillary mural cells that regulate blood-brain barrier (BBB), cerebral blood flow (CBF) and neuronal functions. Pericyte loss is found in AD; yet, their role in AD pathophysiology and the therapeutic potential of cell-based pericyte therapy for AD remain largely unknown. For this proposal, we generated a novel inducible pericyte-specific Cre line, and pericyte-CreER; iDTR mice carrying Cre-dependent human diphtheria toxin receptor (DTR), which leads to pericyte ablation after DT treatment. After partial (60%) pericyte ablation, we preliminarily observed rapidly evolving ischemia-like CBF reductions, BBB breakdown, and rapid loss of neurons and behavioral deficits. We show preliminarily that iPSC-PC resemble forebrain pericytes in gene expression and function such as maintenance of BBB integrity, homing to and integration with host (mouse) blood vessels, role in A? and tau clearance, and neuronal protective role. Using state-of-the-art molecular and imaging methodology this project will test novel hypothesis that loss of brain pericytes provides a pathogenic link to age-dependent AD-like vascular, neuronal, A? and tau pathology, whereas cell therapy with iPSC-PC will slow down and/or reverse vascular and neurodegenerative changes, A? and tau pathology. We will study CBF and BBB changes (AIM 1) and neuron loss and behavior (AIM 2) in pericyte-CreER; iDTR mice after pericyte ablation with DT, and generate proof-of-concept data for use of iPSC-PC therapy for vascular and neuronal disorders. We will also determine CBF, BBB, A? and/or tau pathology, neuron loss and behavior in 5xFAD (AIM 3) and P301S Tg tau (AIM 4) mice crossed with pericyte-CreER; iDTR mice after pericyte ablation with DT, and generate proof-of-concept data for use of iPSC-PC cell therapy for vascular, neuronal, A? and tau disorders in amyloid and tau models with normal and accelerated pericyte loss. Male and female mice at different ages will be used. Understanding the role of pericytes in the pathogenesis and treatment of vascular, neuronal, A? and tau disorders will have profound implications for our understanding of AD pathophysiology, and development of new, non-neuronal pericyte-based cell therapy for AD and related neurodegenerative disorders.